Esmolol hydrochloride (methyl-3-[4-(2-hydroxy-3-isopropylamino) propoxy]phenylpropionate hydrochloride) is a 50:50 racemic mixture of S- and R-isomers. Esmolol hydrochloride is a fast-acting beta-blocker used for treatment of cardiac disorders such as tachycardia, including supraventricular tachycardia, intraoperative tachycardia and postoperative tachycardia, and hypertension. Most currently available beta-blockers have relatively long onset times. However, it is often desirable in the critical care setting to quickly reduce rate and/or improve rhythmicity during a cardiac crisis, e.g., during or shortly after a myocardial infarction. Conventional beta-blocking agents can be employed for such treatment, but their relatively long onset times can prevent a clinician from effectively titrating the dose quickly, e.g., when a patient is in crisis. Because of esmolol hydrochloride's relatively fast onset time, feedback is immediate and, thus, dosing can be advantageously adjusted quickly according to the patient's response.
Esmolol hydrochloride differs from conventional beta-blocking compounds in that it contains an ester functional group which can be rapidly hydrolyzed. Esmolol hydrochloride has a short duration in vivo due to the presence of the ester group and is indicated for the rapid control of ventricular rate in patients with supraventricular tachycardia (i.e., atrial fibrillation or atrial flutter) in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Esmolol hydrochloride is also indicated for the treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia, and in the postoperative period. Esmolol hydrochloride is typically administered by infusion.
A shortcoming of esmolol hydrochloride involves the development of hypotension in a significant number of patients to whom it is administered. Hypotension is listed on the packaging insert as a commonly occurring adverse event associated with esmolol treatment. See Esmolol Hydrochloride Injection Ready-to-use 10 mL Vials, packaging insert (Baxter Healthcare Corporation); see also Byrd et al., JACC, 3:394-9 (1984). In fact, 20-50% of patients treated with esmolol hydrochloride experienced hypotension in clinical trials. See Esmolol Hydrochloride Injection Ready-to-use 10 mL Vials, packaging insert. Hypotension can occur at any dose but is dose-related so that esmolol hydrochloride doses greater than 200 μg/kg/min are generally not recommended. Id. Hypotension can cause oxygen deprivation in the brain and vital organs, ultimately resulting in shock. Hypotension can also cause dizziness and fainting. Currently, hypotension is generally controlled in patients to whom esmolol is administered by carefully titrating the infusion rate of the drug. It is particularly important to closely monitor patients whose pretreatment blood pressure is low. A desired higher infusion rate often cannot be used to lower the heart rate of a patient in stress because of concern that hypotension may develop and/or because of the actual development of hypotension. As a result, esmolol hydrochloride administration often takes longer to achieve its desired therapeutic effect than it otherwise would by utilizing the desired higher infusion rate.
In view of the foregoing, it would be advantageous to retain the efficacious beta-blockade effects of esmolol hydrochloride while minimizing the bothersome hypotension that occurs with significant frequency in esmolol hydrochloride administration.